The invention is directed to a device for delivering follicle stimulating hormone solution, and more specifically to a one-time use and variable dosage, auto-injector device for self-injection of a preservative-free formulation of follicle stimulating hormone solution.
Follicle stimulating hormone solution (FSH) is used to treat infertility in women by stimulating one or more ovarian follicles (and the egg contained within the follicle) to develop and mature. FSH treatment is used when a woman desires pregnancy and her ovaries can produce a follicle but physiologic levels of FSH are not sufficient to make the follicle mature to ovulation necessary for a desired pregnancy. FSH treatment is also used to stimulate the development of multiple follicles and eggs for Assisted Reproductive Technology procedures (including in vitro fertilization) to achieve a desired pregnancy. Follicle stimulating hormone can also be used to treat infertility in men by increasing the production of sperm.
Self-administered treatment of FSH has been in existence for well over 10 years. Two well-known approved FSH formulations are EMD Serono, Inc.'s Gonal-f® and Merck & Co. Inc.'s Follistim®. Both products were approved in 1997 by the United States Food and Drug Administration (FDA) as lyophilized (or powder) formulations, requiring reconstitution with a diluent before injection. A typical FSH treatment plan requires one or two injections per day over a several-day period. For most patients, visiting a doctor's office for daily or twice-daily administration of FSH is completely impractical. Accordingly, the industry has supplied pen-like injection devices with liquid formulations of FSH that were approved in 2004 (Gonal-f RFF® pen and Follistim AQ® cartridge to be used with the Follistim Pen®), typically adapted from insulin injecting devices, for use by the patient to self-administer doses of FSH. These devices however include several deficiencies which add complexity to self-administration of FSH and the potential for needle or injection anxiety, dosing errors or lack of compliance.
These pens are remarkably difficult to use for the average person. Each prior art device requires several steps which, if not performed correctly and in the correct order, can result in a misadministration of FSH. Below are included examples of the required user steps for two pen injection devices supplied by industry leaders of self-administered FSH treatment.
Follistim ® AQ Cartridge Gonal F ® RFF (follitropin beta injection)/(“Gonal-F”) Puregon ® (“Puregon”) Pen by Serono:Pen by Merck:1.Examine the Gonal F pen toRemove the protective cap from themake sure the medication is clearPuregon pen2.Remove the white pen capUnscrew the blue pen body from theyellow cartridge holder3.Wipe the threaded tip of the penInspect the Puregon drug cartridge towith an alcohol swabmake sure it is clear4.Remove the peel tab from theClean the rubber stopper of the outer needle capPuregon drug cartridge with an alcohol pad5.Hold the outer needle cap firmlyInsert the Puregon cartridge into thein one handyellow cartridge holder6.Press the threaded tip of the pen Insert the blue pen body into the into the open end of the outeryellow cartridge holder with the needle capblack rod pressing against the rubber piston of the cartridge7.Twist the pen clockwise until the Screw the yellow cartridge holderneedle is securely attachedtoward the blue body making sure that the arrow on the cartridge holder points to the middle of the alignment mark on the cartridge body8.Remove the outer needle cap byCheck that there is no gap betweenpulling it straight offthe yellow cartridge holder and the pen body9.To prime the pen for the first use,Clean the open end of the cartridgeset the dose arrow to 37.5holder and the rubber stopper of thecartridge with an alcohol pad10.Pull out the white injection buttonRemove the paper seal from the BDas far as it will goUltra Fine Pen Needle Unit11.Remove the inner needle capPush the end of the yellow cartridgeholder into the outer needle shield and screw on tightly12.Hold the pen so the needle pointsUse an alcohol pad to clean the areaupwardwhere the needle will be inserted13.Gently tap the pre-filled reservoirRemove the outer needle shield with your finger to let any airleaving the inner needle shield in bubbles rise to the topposition14.Push in the white injection buttonRemove the inner needle shieldand hold until you hear a click15.A small amount of liquid shouldHold the pen with the needle appear from the needle tip whichpointing upward and tap the means the pen is now primed andcartridge holder gently with yourready for usefinger to help the air bubbles rise to the top of the cartridge16.Replace the inner needle capAt this point, you should see adroplet forming at the top of the needle17.To set the dose, turn the dosageIf you do not see a droplet, dial thedial so your prescribed dose linesdosage knob one mark on the dosageup with the prescribed dose arrowscale until you hear a click18.Load the dose by pulling out theWith the needle pointing upward, injection button as far as it will gopush the orange injection button inall the wayand then check the needle to make sure the drop of fluid comes out19.Confirm the correct dose byTurn the dosage knob until the looking at the last fully visible red desired dose is in the middle of the flat arrow on the injection buttondosage windowwhich indicates the dose that isloaded and ready to be injected20.Clean the recommended injectionPinch up a large area of the cleansedsite with an alcohol swabskin between your finger and thumb21.Remove the inner needle capWith your other hand, insert the needle directly into the skin at a 90-degree angle22.Hold the pen in one hand and Fully press the end of the orangewith the other hand pinch the skininjection button and wait five around the injection siteseconds before removing the needlefrom the skin23.To inject, insert the needle intoPlace the outer needle shield on the the skin at a 90-degree angletable with the opening pointing up24.Once the needle is inserted,Insert the needle attached to the release the pinched skin and pushPuregon pen into the opening of the injection button until it stopsthe outer needle shield and push clickingdown firmly25.Keep the needle in the skin for atGrip the outer needle shield and use least five seconds and thenit to unscrew the needleremove the needle26.Hold the pen firmly by the clearPlace the needle with the outer drug reservoir to recap the needleneedle shield in the Sharps with the outer needle shield tocontaineravoid needle pricking and replacethe outer needle cap27.Grip the outer needle cap firmlyPut the blue cap back on the and unscrew the pen from thePuregon penneedle by turningcounterclockwise28.Dispose of the used needle in aStore the pen and cartridge for theSharps containernextdose29.Recap the pen
Gonal-f currently holds approximately 53% share of the market (EU, North America, & Japan), while Follistim® (also known as Puregon® outside of the US) holds approximately 47%. The producers of the corresponding pens for these products directly compete with one another, but have yet to improve these devices beyond the complex steps noted above. The complexity of self-administration of needles has been identified in published papers as a problem with FSH treatment. While the currently marketed pens may offer less complexity over a simple needle, syringe, and vial, they still have not fully addressed the needs of the patient population. One of the pens is a rebranded pen originally intended for use with insulin injections. Accordingly, the dosing markings on the pen have no specific relationship to the doses required for FSH injections, and must be interpreted accordingly. The dose increments available are extremely small and bear no relationship to commonly used doses of FSH. For example, the Follistim Pen® has 54 dose settings available. This is because this pen is actually a rebranded insulin pen in which each dose increment corresponds to 1 international unit (IU) of insulin. Accordingly, only very few dose settings (approximately 10%) of the available doses are used. This only adds to user confusion and the tendency to commit dosing errors.
The existing FSH pens are designed as multi-use pens. One available pen is supplied with a specified quantity of protein as measured in IUs that is typically more than what is needed for a single administration. Another available pen requires assembly with a multi-use cartridge that typically contains more IUs of the protein than what is required for a single administration. The advantage of a multi-use pen is that a patient can use the same pen for more than one dose, lessening some of the complex steps involved for a subsequent injection with the same pen. However, one pen or cartridge is not sufficient to complete one treatment cycle, requiring a patient to use at least 2-3 pens or cartridges and as many as 14 pens or cartridges to complete their treatment cycle. The total number of pens or cartridges to be used cannot be predicted before treatment because the daily dose and the total number of days to complete a course of therapy vary according to the patient's clinical response. This often leads to waste of the remaining medication in one or more pens or cartridges or the need to give 2 separate injections to administer one dose. Accordingly, a patient must implement a dosing routine which works around the available amount of FSH solution from their prescribed pens or cartridges. The patient must also be responsible for calculating the difference between the total dose contained in a pen or cartridge minus the last doses administered from that pen or cartridge and the current dose in order to make sure that the pen or cartridge that the patient is currently using has enough FSH solution to provide the needed dose. For chronic conditions such as diabetes, this approach may be appropriate because the patient has many months to years to develop the technique for proper dose selection and use of the pens. However, for a 9-14 day treatment cycle for treatment of infertility in healthy women attempting to get pregnant, the existing options are far more complex than they need to be.
Complexity of use is not the only long-felt problem which has not been addressed by the industry. The use of a needle in general can trigger a mental condition that is known as needle or injection anxiety. Simple viewing and handling of a needle can cause many patients to experience symptoms of anxiety or an enhanced physiologic response that results in nausea, lightheadedness, and fainting and may trigger an enhanced painful response. In addition, the need for the patient to manually depress the plunger rod of these pen-injectors is a reminder to the patient that the patient is injecting himself or herself with medication adding to the potential anxiety. Some patients will simply not seek out the therapy due to their fear of or anxiety with needles and injections. Others will have their partners administer to them the injection. Needle and injection anxiety can accordingly result in a general discomfort and fear which leads to undue stress, needle stick accidents, lack of compliance, lightheadedness or fainting, and lack of seeking treatment.
Further, many of the pens or cartridges utilize formulations of FSH which are intended to be saved for multiple uses. This requires formulations which include preservatives, such as benzyl alcohol or m-cresol. The side effect of this, however, can be a painful sensation caused by the injection of the preservative into the patient. This is often described as a burning-like sensation, separate from the pain induced by the needle prick alone. In addition, benzyl alcohol has been associated with significant side effects such as kernicterus and death in newborn babies.
It is clear that there have been long-felt needs which have not been addressed by industry leaders to solve the problems noted above. The problems shown above are not merely separate and distinct, but are interwoven, complex and tangled. Complexity of use is notably a derivative of implementing a reusable pen, or a reusable pen in combination with a reusable FSH cartridge, which requires a new needle for each use. Further, needle or injection anxiety is induced by the need to directly handle and visualize a needle for a reusable pen as well as the need to manually depress the plunger rod. However, needle anxiety cannot be addressed by the current pens, as these pens are required to be reused, and thus require a new needle to be attached and handled for each use. Painful burning sensations induced by preservatives in FSH solutions are also not addressable by the prior art pens because the FSH cartridges need to be used over many treatments. Thus, the use of a preservative in a liquid formulation is necessary to minimize or prevent bacterial overgrowth of the remaining liquid in the pen or cartridge.
All of the noted problems raise safety concerns and may lower the efficacy of the FSH treatment, but also are seen as individual solutions in their own right, which further complicates identification of the issues. The preservatives used in the FSH solutions are seen as beneficial in one aspect because the pens or cartridges can be used multiple times. Further, the pens currently implemented are compatible with syringes and cartridges used with other medical conditions (e.g., insulin cartridges for diabetes) which reduces costs. Thus, one problem enhances or causes another, but is valued in some aspects to address a separate issue. Some of these issues are seen to lower costs, but as the safety issues rise, the detriment to the patient and greater society in bearing these costs is enhanced.
Thus, identification of the problematic issues of self-administration of FSH is complex in that currently implemented features are perceived solutions that actually present further problems in their own right. Accordingly, there is a tendency in the industry to hold on to these features. It would be beneficial to have a device which addresses these issues, while concurrently not detracting from the benefits of the prior art pens. Embodiments of the invention address these and other issues.